PI3K and mTOR Inhibitors in Clinical Development for HNSCC

PI3K and mTOR Inhibitors in Clinical Development for HNSCC

Dr. Christine Chung

Identifying new targets in tumor biology has led to new advances in the clinical development of targeted inhibitors in clinical practice. PI3K is a key enzyme for cellular proliferation, and targeting the PI3K pathway is an active area of clinical research in head and neck squamous cell carcinoma (HNSCC).

During the Sunday, May 31, Education Session “PI3-Kinase: Genomics to Clinical Practice,” the significance of targeting the PI3K pathway was highlighted, with specific emphasis on the therapeutic development in HNSCC.

Rationale for Inhibiting PI3K Pathway in HNSCC

Christine H. Chung, MD, of Johns Hopkins University School of Medicine, chaired the session and first focused on the biology and significance of targeting PI3K in HNSCC.

Given its significance in HNSCC, Dr. Chung discussed the basic biology of the PI3K pathway. She called attention to classes I, II, and III of PI3K, with class I being subdivided in class IA and IB. The active molecule is a heterodimer of a catalytic and a regulatory subunit. The catalytic subunits (a, b, and d) are encoded by genes PIK3CA, PIK3CB, and PIK3CD. The regulatory subunits a, b, and g are encoded by PIK3R1, PIK3R2, and PIK3R3, respectively. The complexity is dictated by the many combinations in which the catalytic and regulatory subunits can pair together.

Bringing PI3K inhibitors to the clinic has focused on the inhibition of PIK3CA. Inhibitors in development may be specific for inhibiting the a or b subunit. Class I pan-PI3K inhibitors are typically not as potent but provide inhibition of all PI3K catalytic subunits. Therapeutic and functional differences and different potencies of each inhibitor are relevant considerations, Dr. Chung said.

“Hot spots” in PIK3CA are seen in up to 11% of HPV-negative HNSCC and in up to 33% of HPV-positive HNSCC. Further complexity arises from whether the mutation affects the “helical domain” (not implicated in the binding of the regulatory molecule, p85) or the “kinase domain” involved in binding p85. She indicated that statistical softwares such as CHASM and VEST may help in predicting functional impact of PIK3CA mutations.

Although the biology strongly suggests that targeting the PI3K pathways should be clinically beneficial, the dramatic response expected of PI3K inhibitors is not borne out in clinical studies.

Dr. Chung advanced several reasons, including “loss of target,” and several potential avenues for the emergence of drug resistance, some of which can activate the PI3b isoform. “Further evaluation is required to determine other genomic abnormalities that co-exist with PIK3CA mutations and to determine the right or optimal combination therapy,” she concluded.

PI3K Pathway Inhibition in Combination Therapy

Dr. Fury began by reviewing clinical data regarding the efficacy and toxicities of mTOR inhibitors in HNSCC. He then reviewed strategies for the development of PI3K inhibitors in combination therapy regimens for this disease.

He provided support from his own clinical phase I research showing that everolimus, an mTOR inhibitor, can be combined with induction chemotherapy and radiation therapy in patients with newly diagnosed HNSCC, with encouraging preliminary efficacy results (2-year progression-free survival rates of 77%-85%, respectively). He also reviewed findings from several groups in which addition of mTOR inhibitors to cytotoxic chemotherapy appears to intensify neutropenia, which led to a follow-up study in which mTOR inhibition was combined with low-dose chemotherapy in patients with advanced HNSCC.

Data from the London Health Sciences Centre pathology database, which suggest that activating PIK3CA mutations may be more common in HPV-positive oropharynx squamous cancer compared with HPV-negative oropharynx squamous cancer, were reviewed. HPV-positive squamous cancers were considered a particularly appropriate setting for the development of this class of drugs.

Among various potential combination therapy options, the potential of vertical inhibition strategies that involve targeting upstream and downstream components of the PI3K pathway were given particular attention. Potent inhibition with the combination of PIK3CA and mTOR inhibitors was suggested from preclinical data. Dr. Fury proposed that an important downstream target in the PI3K pathway in HPV-related cancers could be eIF4E, a key regulator of the translation process and one that is upregulated in active viral hepatitis. He explained that the antiviral agent ribavirin has eIF4E-targeting activity, and that this agent is currently being evaluated in early clinical trials.

Overcoming Cetuximab Resistance in HNSCC

Dr. Silvio Gutkind

J. Silvio Gutkind, PhD, of the National Institute of Dental and Craniofacial Research at the National Institutes of Health, discussed how resistance to cetuximab in HNSCC can be overcome through PIK3CA and mTOR inhibitors.

Given that EGFR is overexpressed in up to 90% of HNSCC lesions, cetuximab, an anti-EGFR antibody, was proven to be effective for treating HNSCC and was the first targeted therapy approved for the treatment of advanced HNSCC in combination with chemotherapy or radiation therapy.

Because receptor tyrosine kinases (RTK) are linked to proliferation and the downstream activation of mTOR, Dr. Gutkind shared data from a pilot, single-arm study confirming the efficacy of rapamycin, an mTOR inhibitor, in patients with untreated stage II-IVA oropharyngeal and oral cavity SCC (Poster 395). In 15 of 16 patients there was a clinical improvement, including tumor shrinkage on visual examination, pain relief, and improvement of tongue mobility. Three patients showed greater than 25% tumor shrinkage by CT. Two patients showed response (1 complete, 1 partial). With significant reduction seen inpS6 and pAKTS473—molecules in the mTOR pathway—this proof-of-concept study supports the notion that mTOR is a target in head and neck cancers.

Dr. Gutkind provided data from his laboratory linking RTKs, PIK3CA, and mTOR. First, he showed that HNSCC xenografts implanted in mice were significantly growth inhibited with cetuximab alone and mTOR inhibitors such as rapamycin and Rad001 alone. However, the combination of the two provided greater antitumor response.

Next, Dr. Gutkind revealed preclinical data showing that PIK3CA or KRAS could confer resistance to cetuximab. Cal27 cells were genetically engineered to express activating mutations in PIK3CA or KRAS—both being downstream of EGFR signaling. In the presence of growth factor, he showed that molecules downstream (e.g., S6 and AKT) of PIK3CA or KRAS were activated (“phosphorylated”). Although addition of cetuximab initially inhibited the Cal27 cells expressing PIK3CA or KRAS, within a month they returned to their initial growth capacity, indicating that cells expressing PIK3CA or KRAS developed resistance to cetuximab.

Similarly, HNSCC-derived cells harboring PIK3CA or HRAS mutations endogenously were insensitive to the antitumor effect of cetuximab. The combination of cetuximab and mTOR inhibitors was much better at inhibiting the growth of these cells compared with an mTOR inhibitor alone.

These data support the rationale of combining cetuximab and mTOR inhibitors for HNSCC lesions with genetic alterations in PI3K and molecules downstream of EGFR. Dr. Gutkind indicated that these preclinical observations will advance into clinical development for the treatment of patients with HNSCC. PIK3CA mutations and multiple mechanisms converging on mTOR signaling can confer resistance to cetuximab, and upfront cetuximab and PI3K/mTOR co-targeting will prevent acquired resistance and preemptively strike the tumor.